The present invention relates to the treatment of certain conditions using a compound of formula I or II, or a pharmaceutically acceptable salt thereof, as defined below. Specifically, the compounds of formulas I and II, and their pharmaceutically acceptable salts, as defined below, exhibit corticotropin-releasing factor (CRF) antagonist activity and are useful in the treatment of cardiovascular or heart related diseases such as hypertension, tachycardia, and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress.
The compounds of formulas I and II, their pharmaceutically acceptable salts, and methods of preparing such compounds and salts are referred to in copending PCT international patent application numbers PCT/IB95/00373 (filed May 18, 1995) and PCT/IB95/00439 (filed Jun. 6, 1995), both of which designate the United States, and in copending U.S. patent applications Ser. No. 08/448,539 (filed Jun. 14, 1995) and Ser. No. 08/481,413 (filed Jun. 15, 1995). PCT international patent application numbers PCT/IB95/00373 and PCT/IB95/00439, and U.S. patent application Ser. Nos. 08/448,539 and 08/481,413, referred to above, are incorporated herein by reference in their entirety.
The foregoing PCT international patent applications and United States patent applications refer to the use of the compounds of formulas I and II in the treatment of illnesses induced or facilitated by corticotropin releasing factor and in the treatment of anxiety, depression, fatigue syndrome, gastrointestinal diseases, headache, pain, cancer, immune dysfunction, hemorrhagic stress, drug addiction, drug and alcohol withdrawal symptoms, fertility problems, stress-induced psychotic episodes, neurodegenerative diseases such as Alzheimer""s disease; irritable bowel syndrome including Crohn""s disease, spastic colon and irritable colon; eating disorders such as anorexia nervosa; and inflammatory disorders such as arthritis, asthma and allergies.
Other CRF antagonists that can be used to treat the disorders recited in the method of this invention are referred to in copending PCT international patent application number PCT/IB95/00318 (filed May 4, 1995), which designates the United States, and in copending U.S. patent application Ser. No. 08/448,534 (filed Jun. 14, 1995) and Ser. No. 08/448,529 (filed Jun. 14, 1995). PCT international patent application number PCT/IB95/00318, and U.S. patent application Ser. Nos. 08/448,534 and 08/448,529, referred to above, are incorporated herein by reference in their entirety.
CRF antagonists are mentioned in U.S. Pat. Nos 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. The importance of CRF antagonists is set out in the literature, e.g., as discussed in U.S. Pat. No. 5,063,245, which is incorporated herein by reference. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also incorporated herein by reference.
This invention relates to a method of treating a disorder selected from cardiovascular or heart related diseases such as hypertension, tachycardia, and congestive heart failure, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus, and colonic hypersensitivity associated with psychopathological disturbance and stress, by administering to a mammal, including a human, In need of such treatment a therapeutically effective amount of a compound of the formula 
or a pharmaceutically acceptable salt thereof, wherein
the dashed line represents an optional double bond;
A is xe2x80x94CR7 or N;
B is xe2x80x94NR1R2, xe2x80x94CR1R2R11, xe2x80x94C(xe2x95x90CR1R12)R2, xe2x80x94NHCR11R1R2, xe2x80x94OCR11R1R2, xe2x80x94SCR11R1R2, xe2x80x94CR11R2OR1, xe2x80x94CR11R2SR1, xe2x80x94C(S)R2, xe2x80x94NHNR1R2, xe2x80x94CR2R11NHR1 or xe2x80x94C(O)R2;
D is: (i) N or xe2x80x94CR10 when a double bond connects E and D and E is xe2x80x94CR4; (ii) xe2x80x94CR10 when a double bond connects E and D and E is N; (iii) xe2x80x94CR8R9, xe2x80x94CHR10, xe2x80x94Cxe2x95x90O, xe2x80x94Cxe2x95x90S, xe2x80x94Cxe2x95x90NH, or xe2x80x94Cxe2x95x90NCH3 when a single bond connects E and D;
E is xe2x80x94CR4 or N when a double bond connects E and D, and E is xe2x80x94CR4R6 or xe2x80x94NR6 when a single bond connects E and D;
Y is N or xe2x80x94CH;
Z is NH, O, S, xe2x80x94N(C1-C2 alkyl) or xe2x80x94CR12R13, wherein R12 and R13 are each, independently, hydrogen, trifluoromethyl or methyl, or one of R12 and R13 is cyano and the other is hydrogen or methyl;
R1 is hydrogen or C1-C6 alkyl which is optionally substituted with one or two substituents independently selected from hydroxy, cyano, nitro, fluoro, chloro, bromo, iodo, CF3, C1-C4 alkoxy, xe2x80x94Oxe2x80x94COxe2x80x94(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94NH(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C4 alkyl), xe2x80x94S(C1-C4 alkyl), xe2x80x94N(C1-C4alkyl)CO(C1-C4 alkyl), xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94CO2(C1-C4 alkyl), xe2x80x94CONH(C1-C4 alkyl), xe2x80x94CON(C1-C4 alkyl)(C1-C2 alkyl), (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, and (C1-C4 alkyl)sulfanyl, and wherein said C1-C6 alkyl, C1-C4 alkoxy and the C1-C4 alkyl moieties in the foregoing R1 groups optionally contain one double or triple bond;
R2 is C1-C6 alkyl, aryl or (aryl)C1-C4 alkyl wherein said aryl and the aryl moiety of said (aryl)C1-C4 alkyl are selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl; or R2 is C3-C8 cycloalkyl or (C3-C8 cycloalkyl)C1-C6 alkyl, wherein one or two of the ring carbons of said cycloalkyl having at least 4 ring members and the cycloalkyl moiety of said (C3-C8 cycloalkyl)C1-C6 alkyl having at least 4 ring members is optionally replaced by an oxygen or sulfur atom or by xe2x80x94NR14 wherein R14 is hydrogen or C1-C4 alkyl; and wherein each of the foregoing R2 groups is optionally substituted by from one to three substituents independently selected from chloro, fluoro and C1-C4 alkyl, or by one substituent selected from bromo, iodo, cyano, nitro, C1-C6 alkoxy, xe2x80x94Oxe2x80x94COxe2x80x94(C1-C4 alkyl), xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94CO2(C1-C4 alkyl), (C1-C4 alkyl)sulfanyl, (C1-C4 alkyl)sulfinyl, and (C1-C4 alkyl)sulfonyl, and wherein said C1-C6 alkyl and the C1-C4 alkyl and C1-C6 alkyl moieties of the foregoing R2 groups optionally contain one carbon-carbon double or triple bond;
or R1 and R2 of said xe2x80x94NR1R2 and said xe2x80x94CR1R2R11 are taken together to form a saturated 5 to 8 member ring, wherein said ring optionally contains one or two carbon-carbon double bonds, and wherein one or two of the ring carbons is optionally replaced by an oxygen or sulfur atom;
R3 is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, hydroxy, amino, SH, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94CH2OH, xe2x80x94CH2OCH3, xe2x80x94O(C1-C4 alkyl), (C1-C4 alkyl)sulfanyl, (C1-C4 alkyl)sulfonyl, or (C1-C4 alkyl)sulfinyl, wherein said C1-C6 alkyl and the C1-C4 alkyl moieties of the foregoing R3 groups optionally contain one double or triple bond and are optionally substituted by from one to three substituents independently selected from hydroxy, amino, C1-C3 alkoxy, xe2x80x94NH(C1-C2 alkyl), xe2x80x94N(C1-C2)2, xe2x80x94NHCOCH3, fluoro, chloro and C1-C3 thioalkyl;
R4 is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, C1-C6 alkoxy, formyl, trifluoromethoxy, xe2x80x94CH2OCH3, xe2x80x94CH2OCH2CH3, xe2x80x94CH2CH2OCH3, xe2x80x94CH2CF3, CF3, amino, nitro, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(CH3)2, xe2x80x94NHCOCH3, xe2x80x94NHCONHCH3, (C1-C4 alkyl)sulfanyl, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, cyano, hydroxy, xe2x80x94CO(C1-C4 alkyl), xe2x80x94CHO, or xe2x80x94CO2(C1-C4 alkyl), wherein said C1-C6 alkyl, C1-C6 alkoxy and the C1-C4 alkyl moieties of the foregoing R4 groups optionally contain one double or triple bond and are optionally substituted with one substituent selected from hydroxy, amino, xe2x80x94NHCOCH3, xe2x80x94NH(C1-C2 alkyl), xe2x80x94N(C1-C2 alkyl)2, xe2x80x94CO2(C1-C4 alkyl), xe2x80x94CO(C1-C4 alkyl), C1-C3 alkoxy, (C1-C3 alkyl)sulfanyl, fluoro, chloro, cyano and nitro;
R5 is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinolyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzoisothiazolyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, azaindolyl, benzoxazolyl, oxazolyl, pyrrolidinyl, thiazolidinyl, morpholinyl, pyridinyl, tetrazolyl, or 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl, wherein said cycloalkyl and bicycloalkyl optionally contain one or two of O, S or xe2x80x94Nxe2x80x94G wherein G is hydrogen, C1-C4 alkyl, C1-C4 alkanoyl, phenyl or benzyl, wherein each of the above R5 groups is optionally substituted by from one to three substituents independenly selected from fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy and trifluoromethyl, or one substituent selected from bromo, iodo, cyano, nitro, amino, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94CO2(C1-C4 alkyl), xe2x80x94CO(C1-C4 alkyl), xe2x80x94SO2NH(C1-C4 alkyl), xe2x80x94SO2N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94SO2NH2, xe2x80x94NHSO2(C1-C4 alkyl), xe2x80x94S(C1-C4 alkyl), and xe2x80x94SO2(C1-C4 alkyl), wherein said C1-C4 alkyl and C1-C6 alkyl moieties of the foregoing R5 groups optionally contain one double or triple bond and are optionally substituted by one or two substituents independently selected from fluoro, chloro, hydroxy, amino, methylamino, dimethylamino and acetyl;
R6 is hydrogen or C1-C6 alkyl, wherein said C1-C6 alkyl is optionally substituted by a single hydroxy, methoxy, ethoxy or fluoro group;
R7 is hydrogen, C1-C4 alkyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, C1-C4 alkoxy, xe2x80x94CO(C1-C4 alkyl), xe2x80x94CO2(C1-C4 alkyl), xe2x80x94OCF3, CF3, xe2x80x94CH2OH, xe2x80x94CH2OCH3 or xe2x80x94CH2OCH2CH3;
R8 and R9 are each, independently, hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy;
or R8 and R9 together form an oxo (xe2x95x90O) group;
R10 is hydrogen, C1-C6 alkyl, fluoro, chloro, bromo, iodo, C1-C6 alkoxy, formyl, amino, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94SOn(C1-C4 alkyl), wherein n is 0, 1 or 2, cyano, carboxy, or amido, wherein said C1-C6 alkyl and the C1-C4 alkyl moieties of the foregoing R10 groups are optionally substituted by one of hydroxy, trifluoromethyl, amino, carboxy, amido, xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94CO2(C1-C4 alkyl), C1-C3 alkoxy, C1-C3 thioalkyl, fluoro, bromo, chloro, iodo, cyano or nitro; and,
R11 is hydrogen, hydroxy, fluoro, or methoxy.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties or combinations thereof.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9ctreatmentxe2x80x9d, as used herein, unless otherwise indicated, includes the treatment, prevention, or inhibition of any disorder enumerated within the method of the invention.
More specific compounds for use in the method of the invention include compounds of formula I or II, or pharmaceutically acceptable salts thereof, wherein: B is xe2x80x94NR1R2, xe2x80x94NHCHR1R2, xe2x80x94CR1R2R11, xe2x80x94SCHR1R2 or xe2x80x94OCHR1R2; R1 is C1-C6 alkyl which is optionally substituted with a single hydroxy, fluoro or C1-C2 alkoxy group and optionally contains one carbon-carbon double or triple bond; R2 is benzyl or C1-C6 alkyl which optionally contains one carbon-carbon double or triple bond, wherein said C1-C6 alkyl and the phenyl moiety of said benzyl are optionally substituted with fluoro, C1-C2 alkyl, or C1-C2 alkoxy; and R11 is hydrogen or fluoro.
Other more specific compounds for use in the method of the invention include compounds of formula I or II, or pharmaceutically acceptable salts thereof, wherein R2 is (aryl)C1-C4 alkyl in which said aryl moiety is phenyl, thienyl, benzofuranyl, furanyl, benzothienyl, thiazolyl, pyridyl or benzothiazolyl.
Other more specific compounds for use in the method of the invention include compounds of formula I or II, or pharmaceutically acceptable salts thereof, wherein B is xe2x80x94NR1R2 or xe2x80x94CHR1R2 in which R1 and R2 are taken together with N or CH to form a 5- or 6-membered ring optionally having sulfur, oxygen, or one more nitrogen in said ring, such as a pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrazinyl or pyrimidyl group.
Other more specific compounds for use in the method of the invention include compounds of formula I or II, or pharmaceutically acceptable salts thereof, wherein B is xe2x80x94NHCHR1R2 or xe2x80x94OCHR1R2, wherein the CHR1R2 moiety is a 5- or 6-membered ring which optionally contains one oxygen or sulfur, such as a tetrahydrofuranyl, tetrahydrothiafuranyl or cyclopentanyl group.
Other more specific compounds for use in the method of the invention include compounds of formula I or II, or pharmaceutically acceptable salts thereof, wherein B is tetrahydrofuranyl, tetrahydrothienyl or thiazolidinyl.
Other more specific compounds for use in the method of the invention include compounds of formula I or II, or pharmaceutically acceptable salts thereof, wherein R3 is methyl, chloro, or methoxy; R4 is methyl, xe2x80x94CH2OH, cyano, trifluoromethoxy, methoxy, trifluoromethyl, chloro, xe2x80x94CO2CH3, xe2x80x94CH2OCH3, xe2x80x94CH2Cl, xe2x80x94CH2F, amino or nitro; R6 is hydrogen, methylsulfinyl, methylsulfanyl, methylsulfonyl, methyl or ethyl; and R5 is phenyl or pyridyl wherein said phenyl or pyridyl is substituted by two or three substituents independently selected from fluoro, chloro, bromo, iodo, C1-C4 alkoxy, trifluoromethyl, (C1-C2 alkoxy)C1-C4 alkyl, C1-C3 hydroxyalkyl, hydroxy, formyl, xe2x80x94CO2(C1-C2 alkyl), (amino)C1-C2 alkyl, xe2x80x94CO(C1-C4 alkyl), and C1-C6 alkyl, wherein said C1-C6 alkyl and said C1-C4 alkyl are optionally substituted by a single hydroxy, C1-C2 alkoxy or fluoro group and optionally contains one carbon-carbon double or triple bond.
For use in the method of the invention, specific compounds of formulas I and II include:
4-(1-ethyl-propoxy)-2,5dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine;
2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;
2-(4-ethyl-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;
3-ethyl-4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;
2-(2,6dimethyl-4-propyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;
4-(1-ethyl-propoxy)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine;
2-(4-ethoxy-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;
2-(4chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propoxy)-3,6-dimethyl-pyridine;
4-(1-methoxymethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridiny-4-yl]-diethyl-amine;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amine;
[2,5-dimethyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-4-yl](1-ethyl-propyl)-amine;
butyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethyl-phenylsulfanyl)-pyridine;
butyl-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-ethyl-amine;
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester;
[3,6-dimethyl-[2-(2,4,6-trimethyl-phenylsulfanyl)-pyridin-4yl-]-ethyl-propyl-amine;
4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-methanol;
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4yl-]ethyl-propyl-amine;
1-(ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin4yl-]-amine;
N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine;
N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;
N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-diamine;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine;
[3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)pyridin-4-yl]-(1-ethyl-propyl)-amine;
[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine;
(1-ethyl-propyl)-[2-methyl-5-nitro-6-(2,4,6-trimethyl-pyridin-3-yloxy)-pyrimidin-4-yl]-amine;
(1-ethyl-propyl)-[3-methoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine;
N-(1-ethyl-propyl)-2-methyl-5-nitro-Nxe2x80x2-(2,4,6-trimethyl-pyridin-3-yl)-pyrimidine-4,6-diamine;
[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethylpyridin-4-yl]-diethyl-amine;
4-(1-ethyl-propoxy)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine;
butyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethyl-amine;
4-(butyl-ethylamino)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one;
4-(1-ethylpropoxy)-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyrimidine;
N-butyl-N-ethyl-2,5-dimethyl-Nxe2x80x2-(2,4,6-trimethylphenyl)-pyrimidine-4,6-diamine;
(1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]amine;
[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;
N4-(1-ethyl-propyl)-6, N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)pyridine-3,4-diamine;
N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine;
6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyridine-4,5-diamine;
[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine; and
6-(ethyl-propyl-amino)-2,7-dimethyl-9-(2,4,6-trimethylphenyl)-7,9-dihydro-purin-8-one.
For use in the method of the invention, specific compounds of formula II wherein E and D are connected by a double bond, E is xe2x80x94CR4, D is xe2x80x94CR10 or N, Y is N, and A is xe2x80x94CR7, include:
butyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-ethylamine;
3,6-dimethyl-4-(tetrahydrofuran-3-yloxy)-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine;
[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4,b]pyridin-4-yl]-(1-methoxymethylpropyl)-amine;
4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine;
(1-ethylpropyl)-[3,5,6-trimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-amine;
4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-b]pyridine;
4-(1-ethylpropoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3b]pyridine; and
4-(1-ethylpropoxy)-2,5-dimethyl-7-(2,6-dimethyl-4-bromophenyl)-7H-pyrrolo[2,3-b]pyridine.
For use in the method of the invention, specific compounds of formula II wherein E and D are connected by a double bond, E is xe2x80x94CR4, and D, Y and A are N, include:
3-{(4-methyl-benzyl)-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-propan-1-ol;
diethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
2-{butyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-tichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}-ethanol;
dibutyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-amine;
butyl-ethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
butyl-ethyl-[6-methyl-3-methylsulfonyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
butyl-cyclopropylmethyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
di-1-propyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
dially-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
butyl-ethyl-[6-chloro-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
butyl-ethyl-[6-methoxy-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
propyl-ethyl-[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;
4-(1-ethyl-propyl)-6-methyl-4-methylsulfanyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine;
2-[3,6dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pydmidin-4-ylamine]-butan-1-ol;
[3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-4-yl]-(1-methylpropyl)amine; and
4-(1-methoxymethylpropoxy)-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidine.
For use in the method of the invention, specific compounds of formula II wherein E and D are connected by a double bond, E is xe2x80x94CR4, D is xe2x80x94CR10, and Y and A are N, include:
n-butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
di-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
ethyl-n-propyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
diethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine;
n-butyl-ethyl-[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine
2-{N-n-butyl-N-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}-ethanol;
4-(1-ethyl-propyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;
n-butyl-[2,5-dimethyl-7-(2,4-dimethylphenyl)-7H-pyrrolo[2,3d]pyrimidin-4-yl]amine;
2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidyl-4-yl]-(1-ethyl-propyl)amine;
2-[-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;
2-(S)-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;
4-(1-ethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;
4-(1-methoxymethyl-propoxy)-2,5,6-trimethyl-7-(2,4,6trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine;
4-(1-ethyl-butyl)-2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo-[2,3-d]pyrimidine;
[7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(1-methoxymethyl-propyl)-amine;
2-[7-(2-bromo-4,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;
2-[7-(4-ethyl-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol;
2-[7-(2-ethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol; and
2-[7-(2-fluoromethyl-4,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-butan-1-ol.
The method of the Invention further comprises the treatment of stroke by administering to a mammal, including a human, in need of such treatment a therapeutically effective amount of a compound of formula II, referred to above, or a pharmaceutically acceptable salt thereof, wherein a double bond connects E and D, D is xe2x80x94CR10 or N, E is xe2x80x94CR4, and Y and A are N. Compounds of formula III, provided below, are the compounds of formula II wherein a double bond connects E and D, D is xe2x80x94CR10 or N, E is xe2x80x94CR4, and Y and A are N. The compounds of formula III are provided below in the claims and are directed to the treatment of stroke.
Whenever reference is made herein to 3- to 8-membered cycloalkyl or 9- to 12-membered bicycloalkyl optionally containing one or two of O, S, or xe2x80x94Nxe2x80x94G, it is understood that the oxygen and sulfur atoms are not adjacent to each other in the cycloalkyl or bicycloalkyl ring system. The three membered cycloalkyl optionally contains just one of O, S, or xe2x80x94Nxe2x80x94G. An example of a six-membered cycloalkyl having o and NH is morpholinyl.
Whenever R2 or R5 is a heterocyclic group, the attachment of the group is through a carbon atom.
In the compounds of formulas I and II, referred to above, certain animal or acetal moieties may not be sufficiently stable for use in the method of the invention. Such unstable compounds may include, for example, a compound of formula I or II wherein B is xe2x80x94NR1R2 and R1 is xe2x80x94CH(OH)CH3. Such unstable compounds will be apparent to those skilled in the art and do not form part of the invention.
Formulas I and II, referred to above, are Intended to include all stereoisomers (e.g., all geometric and optical isomers) as well as racemates of all individual compounds within the depicted genus.